Allogeneic hematopoietic stem cell transplantation (HCT) is a curative option for patients with acute myelogenous leukemia (AML), both primary AML and secondary AML evolving from a pre-existing myelodysplastic syndrome. Despite improvements in HLA genotyping where 10 allele matching is sought to improve HCT outcome, more than 50% of patients experience post-HCT complications such as relapse, CMV reactivation, and GvHD. NK cells can significantly improve risk for each of these outcomes.
Critical to innate immunity against malignantly transformed or virally infected cells, NK cells are controlled by an array of activating and inhibitory signals processed by cell surface receptors, including the KIR (Lanier, Annu Rev Immunol 23:225-274 (2005)). Interaction of inhibitory KIR on the NK cell surface with self-HLA class I antigens on surrounding autologous cells generates an inhibitory signal, sparing killing of autologous cells (Moesta et al., The Journal of Immunology 180(6):3969-3979 (2008)). In addition to the inhibitory KIR, most individuals have multiple activating KIR. Composed of up to 15 inhibitory and activating genes and pseudogenes on a single haplotype, the KIR gene repertoire is remarkably diverse with wide inter-individual genotypic variation. Reminiscent of the polymorphic diversity of the HLA region, each KIR gene has numerous alleles, with KIR3DL1 as the best characterized inhibitory KIR locus (Gardiner et al., J Immunol 166:2992-3001 (2001)). The clinical significance of such KIR gene diversity has focused on immune responses to viral infection (Carrington et al., Cur Top Microbiol Immunol 298:225-257 (2006); Martin et al., Nat Genet 39:733-740 (2007); Martin et al., Nature Genetics 31:429-434 (2002); Kamya et al., J Virol 85:5949-5960 (2011)) and leukemic, within the allogeneic HCT, where interactions between self and non-self occur. AML is the most common indication for allogeneic HCT, and donor NK alloreactivity can exert a potent anti-leukemic effect in this context (Ruggeri et al., Blood 94:333-339 (1999); Ruggeri et al., Science 295(5562):2097-2100 (2002)). Immunogenetics studies in HCT have evaluated the impacts of KIR/HLA compound genotypes predictive of NK alloreactivity on leukemic relapse and survival, identifying several mechanisms responsible for potent NK effects against AML (Ruggeri et al., Blood 94:333-339 (1999); Ruggeri et al., Science 295(5562):2097-2100 (2002); Ruggeri et al., Blood 110:433-440 (2007); Giebel et al., Blood 102(3):814-819 (2003); Hsu et al., Biol Blood Mar Transpl 12:828-836 (2006); Hsu et al., Blood 105:4878-4884 (2005); Cook et al., Blood 103:1521-1526 (2004); Stringaris et al., Biol Blood MarrTranspl 16:1257-1264 (2010); Venstrom et al., Blood 115(15):3162-3165 (2010)). NK effects against MDS are less clear, but may exist, given the pre-leukemic nature of MDS.
It is known that HLA-mismatched transplants capture NK alloreactivity through recognition on the part of donor NK cells of the lack of donor HLA KIR ligands in the recipient (“missing self” activation) (Ruggeri et al., Blood 94:333-339 (1999)). It has recently been shown in HLA-matched HCT, however, that strong anti-leukemic effects are associated with low-inhibitory donor KIR3DL1 allotypes and cognate HLA-Bw4 ligand allotypes (Giglio et al., Biol Blood Marr Transpl (2012)).
The activating KIR genes include KIR2DS1, 2DS2, 2DS3, 2DS4, 2DS5, and the 3DS1 allele of KIR3DL1. KIR2DS1-positive NK cells from HLA-C1 positive donors can mediate anti-leukemic cytotoxicity and reduce relapse post-HCT (Venstrom et al., New England Journal of Medicine 367:805-816 (2012)). Protective effects of the KIR2DS2-containing centromeric partial KIR haplotype (cenB) against relapse have also been reported (Cooley et al., Blood 113:726-732 (2009; Cooley et al., Blood 116:2411-2419 (2010)). Donor KIR3DS1 is also shown to be protective from GvH and transplant-related mortality (TRM) (Venstrom et al., New England Journal of Medicine 367:805-816 (2012); Cooley et al., Blood 113:726-732 (2009); Cooley et al., Blood 116:2411-2419 (2010); Venstrom et al., Blood 115:3162-3165 (2010)). Finally, donor activating KIR are protective from CMV reactivation in the patient post-HCT (Cook et al., Blood 107:1230-1232 (2006)).
The importance of harnessing NK alloreactivity in HCT is apparent. However, how to exploit KIR/HLA genetics for clinical benefit has been an elusive goal in allogeneic HCT, partly due to gaps in knowledge regarding the biology of KIR genes and alleles in the context of HLA.